Calpain 12 function revealed through the study of an atypical case of autosomal recessive congenital ichthyosis

Ron Bochner, Liat Samuelov, Ofer Sarig, Qiaoli Li, Christopher A Adase, Ofer Isakov, Natalia Malchin, Dan Vodo, Ronna Shayevitch, Alon Peled, Benjamin D. Yu, Gilad Fainberg, Emily Warshauer, Noam Adir, Noam Erez, Andrea Gat, Yehonatan Gottlieb, Tova Rogers, Mor Pavlovsky, Ilan Goldberg & 9 others Noam Shomron, Aileen Sandilands, Linda E. Campbell, Stephanie MacCallum, W. H. Irwin McLean, Gil Ast, Richard L. Gallo, Jouni Uitto, Eli Sprecher

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Abstract

Congenital erythroderma is a rare and often life-threatening condition, which has been shown to result from mutations in several genes encoding important components of the epidermal differentiation program. Using whole exome sequencing, we identified in a child with congenital exfoliative erythroderma, hypotrichosis, severe nail dystrophy and failure to thrive, two heterozygous mutations in ABCA12 (c.2956C>T, p.R986W; c.5778+2T>C, p. G1900Mfs*16), a gene known to be associated with 2 forms of ichthyosis, autosomal recessive congenital ichthyosis and harlequin ichthyosis. Because the patient displayed an atypical phenotype, including severe hair and nail manifestations, we scrutinized the exome sequencing data for additional potentially deleterious genetic variations in genes of relevance to the cornification process. Two mutations were identified in CAPN12, encoding a member of the calpain proteases: a paternal missense mutation (c.1511C>A; p.P504Q) and a maternal deletion due to activation of a cryptic splice site in exon 9 of the gene (c.1090_1129del ; p.Val364Lysfs*11). The calpain 12 protein was found to be expressed in both the epidermis and hair follicle of normal skin but its expression was dramatically reduced in the patient's skin. Down-regulation of capn12 expression in zebrafish was associated with abnormal epidermal morphogenesis. siRNA knockdown of CAPN12 in three-dimensional human skin models was associated with acanthosis, disorganized epidermal architecture and down-regulation of several differentiation markers, including filaggrin. Accordingly, filaggrin expression was almost absent in the patient skin. Using ex vivo live imaging, siRNA knockdown of calpain 12 in skin from K14-H2B GFP mice led to significant hair follicle catagen transformation compared to controls. In summary, our results indicate that calpain 12 plays an essential role during epidermal ontogenesis and normal hair follicle cycling and that its absence may aggravate the clinical manifestations of ABCA12 mutations.

Original languageEnglish
Pages (from-to)385-393
Number of pages9
JournalJournal of Investigative Dermatology
Volume137
Issue number2
Early online date18 Oct 2016
DOIs
Publication statusPublished - Feb 2017

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Ichthyosis
Calpain
Skin
Hair Follicle
Exfoliative Dermatitis
Exome
Nails
Mutation
Genes
Small Interfering RNA
Down-Regulation
Hypotrichosis
Lamellar Ichthyosis
Failure to Thrive
RNA Splice Sites
Gene encoding
Differentiation Antigens
Zebrafish
Missense Mutation
Morphogenesis

Cite this

Bochner, Ron ; Samuelov, Liat ; Sarig, Ofer ; Li, Qiaoli ; Adase, Christopher A ; Isakov, Ofer ; Malchin, Natalia ; Vodo, Dan ; Shayevitch, Ronna ; Peled, Alon ; Yu, Benjamin D. ; Fainberg, Gilad ; Warshauer, Emily ; Adir, Noam ; Erez, Noam ; Gat, Andrea ; Gottlieb, Yehonatan ; Rogers, Tova ; Pavlovsky, Mor ; Goldberg, Ilan ; Shomron, Noam ; Sandilands, Aileen ; Campbell, Linda E. ; MacCallum, Stephanie ; McLean, W. H. Irwin ; Ast, Gil ; Gallo, Richard L. ; Uitto, Jouni ; Sprecher, Eli. / Calpain 12 function revealed through the study of an atypical case of autosomal recessive congenital ichthyosis. In: Journal of Investigative Dermatology. 2017 ; Vol. 137, No. 2. pp. 385-393.
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title = "Calpain 12 function revealed through the study of an atypical case of autosomal recessive congenital ichthyosis",
abstract = "Congenital erythroderma is a rare and often life-threatening condition, which has been shown to result from mutations in several genes encoding important components of the epidermal differentiation program. Using whole exome sequencing, we identified in a child with congenital exfoliative erythroderma, hypotrichosis, severe nail dystrophy and failure to thrive, two heterozygous mutations in ABCA12 (c.2956C>T, p.R986W; c.5778+2T>C, p. G1900Mfs*16), a gene known to be associated with 2 forms of ichthyosis, autosomal recessive congenital ichthyosis and harlequin ichthyosis. Because the patient displayed an atypical phenotype, including severe hair and nail manifestations, we scrutinized the exome sequencing data for additional potentially deleterious genetic variations in genes of relevance to the cornification process. Two mutations were identified in CAPN12, encoding a member of the calpain proteases: a paternal missense mutation (c.1511C>A; p.P504Q) and a maternal deletion due to activation of a cryptic splice site in exon 9 of the gene (c.1090_1129del ; p.Val364Lysfs*11). The calpain 12 protein was found to be expressed in both the epidermis and hair follicle of normal skin but its expression was dramatically reduced in the patient's skin. Down-regulation of capn12 expression in zebrafish was associated with abnormal epidermal morphogenesis. siRNA knockdown of CAPN12 in three-dimensional human skin models was associated with acanthosis, disorganized epidermal architecture and down-regulation of several differentiation markers, including filaggrin. Accordingly, filaggrin expression was almost absent in the patient skin. Using ex vivo live imaging, siRNA knockdown of calpain 12 in skin from K14-H2B GFP mice led to significant hair follicle catagen transformation compared to controls. In summary, our results indicate that calpain 12 plays an essential role during epidermal ontogenesis and normal hair follicle cycling and that its absence may aggravate the clinical manifestations of ABCA12 mutations.",
author = "Ron Bochner and Liat Samuelov and Ofer Sarig and Qiaoli Li and Adase, {Christopher A} and Ofer Isakov and Natalia Malchin and Dan Vodo and Ronna Shayevitch and Alon Peled and Yu, {Benjamin D.} and Gilad Fainberg and Emily Warshauer and Noam Adir and Noam Erez and Andrea Gat and Yehonatan Gottlieb and Tova Rogers and Mor Pavlovsky and Ilan Goldberg and Noam Shomron and Aileen Sandilands and Campbell, {Linda E.} and Stephanie MacCallum and McLean, {W. H. Irwin} and Gil Ast and Gallo, {Richard L.} and Jouni Uitto and Eli Sprecher",
note = "This study was supported in part by a generous donation of the Ram family (ES), by the National Institutes of Health Support (CA) (5T32AR062496-03) and by a Wellcome Trust Strategic Award (098439/Z/12/Z to W.H.I.M.).",
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language = "English",
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pages = "385--393",
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Bochner, R, Samuelov, L, Sarig, O, Li, Q, Adase, CA, Isakov, O, Malchin, N, Vodo, D, Shayevitch, R, Peled, A, Yu, BD, Fainberg, G, Warshauer, E, Adir, N, Erez, N, Gat, A, Gottlieb, Y, Rogers, T, Pavlovsky, M, Goldberg, I, Shomron, N, Sandilands, A, Campbell, LE, MacCallum, S, McLean, WHI, Ast, G, Gallo, RL, Uitto, J & Sprecher, E 2017, 'Calpain 12 function revealed through the study of an atypical case of autosomal recessive congenital ichthyosis', Journal of Investigative Dermatology, vol. 137, no. 2, pp. 385-393. https://doi.org/10.1016/j.jid.2016.07.043

Calpain 12 function revealed through the study of an atypical case of autosomal recessive congenital ichthyosis. / Bochner, Ron; Samuelov, Liat; Sarig, Ofer; Li, Qiaoli; Adase, Christopher A; Isakov, Ofer; Malchin, Natalia; Vodo, Dan; Shayevitch, Ronna; Peled, Alon; Yu, Benjamin D.; Fainberg, Gilad; Warshauer, Emily; Adir, Noam; Erez, Noam; Gat, Andrea; Gottlieb, Yehonatan; Rogers, Tova; Pavlovsky, Mor; Goldberg, Ilan; Shomron, Noam; Sandilands, Aileen; Campbell, Linda E.; MacCallum, Stephanie; McLean, W. H. Irwin; Ast, Gil; Gallo, Richard L.; Uitto, Jouni; Sprecher, Eli (Lead / Corresponding author).

In: Journal of Investigative Dermatology, Vol. 137, No. 2, 02.2017, p. 385-393.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Calpain 12 function revealed through the study of an atypical case of autosomal recessive congenital ichthyosis

AU - Bochner, Ron

AU - Samuelov, Liat

AU - Sarig, Ofer

AU - Li, Qiaoli

AU - Adase, Christopher A

AU - Isakov, Ofer

AU - Malchin, Natalia

AU - Vodo, Dan

AU - Shayevitch, Ronna

AU - Peled, Alon

AU - Yu, Benjamin D.

AU - Fainberg, Gilad

AU - Warshauer, Emily

AU - Adir, Noam

AU - Erez, Noam

AU - Gat, Andrea

AU - Gottlieb, Yehonatan

AU - Rogers, Tova

AU - Pavlovsky, Mor

AU - Goldberg, Ilan

AU - Shomron, Noam

AU - Sandilands, Aileen

AU - Campbell, Linda E.

AU - MacCallum, Stephanie

AU - McLean, W. H. Irwin

AU - Ast, Gil

AU - Gallo, Richard L.

AU - Uitto, Jouni

AU - Sprecher, Eli

N1 - This study was supported in part by a generous donation of the Ram family (ES), by the National Institutes of Health Support (CA) (5T32AR062496-03) and by a Wellcome Trust Strategic Award (098439/Z/12/Z to W.H.I.M.).

PY - 2017/2

Y1 - 2017/2

N2 - Congenital erythroderma is a rare and often life-threatening condition, which has been shown to result from mutations in several genes encoding important components of the epidermal differentiation program. Using whole exome sequencing, we identified in a child with congenital exfoliative erythroderma, hypotrichosis, severe nail dystrophy and failure to thrive, two heterozygous mutations in ABCA12 (c.2956C>T, p.R986W; c.5778+2T>C, p. G1900Mfs*16), a gene known to be associated with 2 forms of ichthyosis, autosomal recessive congenital ichthyosis and harlequin ichthyosis. Because the patient displayed an atypical phenotype, including severe hair and nail manifestations, we scrutinized the exome sequencing data for additional potentially deleterious genetic variations in genes of relevance to the cornification process. Two mutations were identified in CAPN12, encoding a member of the calpain proteases: a paternal missense mutation (c.1511C>A; p.P504Q) and a maternal deletion due to activation of a cryptic splice site in exon 9 of the gene (c.1090_1129del ; p.Val364Lysfs*11). The calpain 12 protein was found to be expressed in both the epidermis and hair follicle of normal skin but its expression was dramatically reduced in the patient's skin. Down-regulation of capn12 expression in zebrafish was associated with abnormal epidermal morphogenesis. siRNA knockdown of CAPN12 in three-dimensional human skin models was associated with acanthosis, disorganized epidermal architecture and down-regulation of several differentiation markers, including filaggrin. Accordingly, filaggrin expression was almost absent in the patient skin. Using ex vivo live imaging, siRNA knockdown of calpain 12 in skin from K14-H2B GFP mice led to significant hair follicle catagen transformation compared to controls. In summary, our results indicate that calpain 12 plays an essential role during epidermal ontogenesis and normal hair follicle cycling and that its absence may aggravate the clinical manifestations of ABCA12 mutations.

AB - Congenital erythroderma is a rare and often life-threatening condition, which has been shown to result from mutations in several genes encoding important components of the epidermal differentiation program. Using whole exome sequencing, we identified in a child with congenital exfoliative erythroderma, hypotrichosis, severe nail dystrophy and failure to thrive, two heterozygous mutations in ABCA12 (c.2956C>T, p.R986W; c.5778+2T>C, p. G1900Mfs*16), a gene known to be associated with 2 forms of ichthyosis, autosomal recessive congenital ichthyosis and harlequin ichthyosis. Because the patient displayed an atypical phenotype, including severe hair and nail manifestations, we scrutinized the exome sequencing data for additional potentially deleterious genetic variations in genes of relevance to the cornification process. Two mutations were identified in CAPN12, encoding a member of the calpain proteases: a paternal missense mutation (c.1511C>A; p.P504Q) and a maternal deletion due to activation of a cryptic splice site in exon 9 of the gene (c.1090_1129del ; p.Val364Lysfs*11). The calpain 12 protein was found to be expressed in both the epidermis and hair follicle of normal skin but its expression was dramatically reduced in the patient's skin. Down-regulation of capn12 expression in zebrafish was associated with abnormal epidermal morphogenesis. siRNA knockdown of CAPN12 in three-dimensional human skin models was associated with acanthosis, disorganized epidermal architecture and down-regulation of several differentiation markers, including filaggrin. Accordingly, filaggrin expression was almost absent in the patient skin. Using ex vivo live imaging, siRNA knockdown of calpain 12 in skin from K14-H2B GFP mice led to significant hair follicle catagen transformation compared to controls. In summary, our results indicate that calpain 12 plays an essential role during epidermal ontogenesis and normal hair follicle cycling and that its absence may aggravate the clinical manifestations of ABCA12 mutations.

U2 - 10.1016/j.jid.2016.07.043

DO - 10.1016/j.jid.2016.07.043

M3 - Article

VL - 137

SP - 385

EP - 393

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

SN - 0022-202X

IS - 2

ER -